Enteric coated products are designed to remain intact in the stomach and then to release the active substance in the intestine. Enteric coating can be applied to solid dosage forms, such as granules, pellets, capsules, or tablets. The purpose of enteric coating is to protect the stomach from irritating active compounds such as aspirin, or to improve drug bioavailability by preventing degradation of acid or gastric enzyme labile drugs. Enteric coatings have been developed for more than one century. The first real enteric coating was believed to use keratin by Unna in 1884. Some of the earlier coatings depended on the enzymatic breakdown or emulsifying effect of the films in the small intestine, such as enteric films based on stearic acid.
Almost all the currently used enteric materials are synthetic or modified natural polymers containing ionizable carboxylic groups. In the low pH environment of the stomach, the carboxylic groups remain un-ionized, and the polymer coatings remain insoluble. In the intestine, the pH increases to 5 and above, allowing the carboxylic groups on the polymeric coating materials to ionize, and the polymer coatings to disintegrate or dissolve, releasing their contents. Based on the purpose of an enteric coating, an ideal enteric coating should possess the following properties: 1. Must resist disintegration or dissolution in the stomach for as long as the dosage form remains there; 2. Must dissolve or disintegrate rapidly in the small intestine; 3. Must be physically and chemically stable during storage; 4. Must be non-toxic; 5. Must be easily applied as a coating; 6. Must be economical.
Table 1 shows some commonly used enteric-coating materials for upper small intestinal drug release.
AbbreviationTypeSolubilityCellulose acetateCAPSoluble in intestinalphthalatefluid from pH 6.0Polyvinyl acetatePVAPSoluble in intestinalphthalatefluid from pH 5.5HydroxypropylHPMCPHP-50Soluble in intestinalmethylcellulosefluid from pH 5.0phthalateHP-55Soluble in intestinalfluid from pH 5.5Poly-methacrylatesEudragit ®Soluble in intestinalL 100-55fluid from pH 5.5Eudragit ®Soluble in intestinalL 30 D-55fluid from pH 5.5Eudragit ®Soluble in intestinalL 100fluid from pH 6.0
It is commonly believed that enteric-coated dosage forms, coated with low dissolution threshold pH polymers such as polyvinyl acetate phthalate, cellulose acetate phthalate or Eudragit® L 100-55, rapidly disintegrate on entry into the small intestine, however, this is not the case.
There is indeed a discrepancy between in vitro and in vivo performance of enteric coatings. For those enteric-coated dosage forms, coated with low dissolution threshold pH polymers, in vitro disintegration always occurs rapidly within few minutes in simulated intestinal pH. In addition, the in vitro dissolution studies normally require that when the enteric-coated products were placed in pH 6.8 buffer, greater than 80% of the drug should be released within 45 min, but in most cases the dissolution time is much shorter than that. However, there is a major discrepancy between in vitro dissolution data and in vivo performance of enteric-coated dosage forms. It can take up to 2 h or 1-2 h or more for the enteric-coated products to disintegrate after gastric emptying.
As small intestinal transit time is of the order of 3-4 hours, disintegration and drug release from such enteric-coated dosage forms will occur in the distal small intestine. In some cases, such delay of drug release from enteric-coated dosage forms could lead to ineffective drug therapy. For example, enzyme supplements constitute the primary approach to treating pancreatic insufficiency of those patients with Cystic Fibrosis (CF). Since patients with CF have lower postprandial duodenal pH compared with healthy people, the enzyme release from conventional enteric-coated dosage forms takes approximately 100 min after gastric emptying. Comparing this release time to the usual small intestine transit time, it appears that as much as half the available contact time between chyme and enzymes could be lost, leading to an insufficient enzyme effect. In addition, for a number of actives, the optimum site of absorption is the upper part of the small intestine. Delayed drug release to distal small intestine could decrease the bioavailability of these drugs in conventional enteric-coated formulations. For instance, the bioavailability of levodopa could be improved by loading high concentrations of the drug at the upper part of the small intestine. An enteric-coated system that releases its drug load promptly on entry into the small intestine would therefore be highly desirable. Such systems would also be of benefit for drugs that are absorbed throughout the small intestine, in terms of rapid onset of action.
The document WO 2007/006353 discloses the use of a partially neutralized anionic (meth)acrylate copolymer comprising radically polymerized units of 25 to 95 percent by weight C1- to C4-alkyl esters of acrylic or of methacrylic acid and 5 to 75 percent by weight of (meth)acrylate monomers having an anionic group, at least 4% of which are neutralized by means of a base, for producing a medicament that is provided with an active substance-containing core and is coated with the partially neutralized, anionic (meth)acrylate copolymer. Said medicament releases at least 30 percent of the active substance contained therein in 30 minutes at a pH at which the active substance is sufficiently soluble and stable and at which the corresponding medicament that is coated with the non-neutralized anionic (meth)acrylate polymer releases less than 10 percent of the active substance contained therein.
The document US 2005/0271778 describes a method for producing pharmaceuticals wherein in the case of gastric resistant solid dosage forms comprising an anionic (meth)acrylate copolymer for the protection of an acid-sensitive active substance contained in the core said polymer is applied to form a gradient in respect to the degree of neutralization of the anionic groups across the thickness of the coating. In the inner region of the coating the anionic groups of the polymer are neutralized to protect the acid labile active substance. The degree of neutralization is decreasing towards the outer region of the coating in order to achieve a gastric resistance of the solid dosage form. In the case of alkali-sensitive solid dosage forms comprising a cationic (meth)acrylate copolymer, for the protection of an alkali-sensitive active substance said cationic polymer is applied to form a gradient in respect to the degree of neutralization of the cationic groups across the thickness of the coating. In the inner region of the coating the cationic groups of the polymer are neutralized to protect the alkali-sensitive active substance. The degree of neutralization of the cationic groups is decreasing towards the outer region of the coating. However, this document does not give any suggestion of how to accelerate the release rate of the active substance.
The document US 2004/0028737 describes enteric coated stable oral pharmaceutical compositions of acid unstable drugs, wherein the enteric coating is a bilayer with a pH gradient across its thickness comprising an inner layer of neutral or near neutral pH 7 to 7.5 and an outer layer of acidic pH 2 to 6. The intention of this document is to achieve stabilization of the acid-sensitive drug. This document does not give any suggestion of how to accelerate the release rate of the active substance.
The document WO 2005/044240 describes a stable formulation for the acid-sensitive lansoprazole, wherein the substrate comprising lansoprazole is coated with a subcoating layer containing an alkaline agent, and an enteric coating on top of this subcoating layer. The document further discloses that as alkaline agent organic basic salts, like sodium stearate, or inorganic basic salts, such as sodium hydrogen carbonate, or other inorganic basic salts which are not water soluble are used. Here again the intention of this state of art is to achieve stabilization of the acid-sensitive drug lansoprazole. This document does not give any suggestion of how to accelerate the release rate of the active substance.
The enteric coated products of this state of art are designed to remain intact in the stomach and then to release the active substance in the upper intestine. The actual observation is that solid dosage forms having the enteric coatings of the state of art do not rapidly disintegrate on entry into the small intestine. Since the small intestinal transit time is of the order of 3 to 4 hours disintegration and drug release from such enteric-coated dosage forms will occur in the distal small intestine. However, this delay of drug release from enteric-coated dosage forms could lead to ineffective drug therapy.
Thus the aim is to provide solid dosage forms with enteric coatings which more rapidly disintegrate on the entry into the small intestine, meaning at an earlier time point when transferred from the stomach having a pH of around 1 to 3.5 to the entry of the intestine having a pH of around 5.5 to 7.0 (compared to more distal sections of the small intestine having a pH of 6.0 to 7.5.